Myelin basic protein (MBP) and proteolipid protein (PLP) are major proteins of compact CNS myelin, whereas myelin-associated glycoprotein (MAG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) are mainly localized in associated oligodendroglial membranes. These 4 myelin proteins are differently affected in various dysmyelinating, demyelinating and remyelinating circumstances, and information about changes in them can increase our understanding of the specific molecular processes going on in each disease. In multiple sclerosis (MS), there is preferential loss of MAG at the edges of the plaques. Much of the MAG remaining in MS tissue is in the form of dMAG, a proteolytic cleavage product formed by a myelin-associated, calcium-activated neutral protease (calpain). MAG loss in MS may be related to this protease. dMAG was also present in some patients with neuro-AIDS (see Z01 NS 02805-05 LMCN). The MAG/dMAG conversion rate in incubated myelin, purified from different species, was greatest in human myelin, rapid in myelin from other primates, and substantially slower in myelin from lower mammals. This suggests that dMAG formation may be relevant to human demyelinating diseases. The MAG/dMAG conversion rate in purified myelin is very sensitive to the Ca2+ concentration in the samples and the levels of some gangliosides. Purified human calpain incubated with purified human MAG totally degraded MAG. In most hypomyelinating mutant animals, MBP and PLP are decreased more than MAG and CNP, due to a greater deficiency of compact myelin than of associated oligodendroglial membranes. This is true regardless of the primary cause of the hypomyelination, e.g. a PLP gene defect (Shaking pup), a cholesterol storage disorder (CSD mice), a congenital virus infection (Border disease in sheep) or in human patients with Niemann-Pick C disease. However, the TAIEP rat expressed decreased amounts of MAG compared to other myelin proteins, and MAG in the younger animals had a higher m.w. when compared to age-matched controls, most likely due to a glycosylation difference in the carbohydrate chains of MAG. In caprine beta-mannosidosis, MAG, CNP and PLP levels were equally decreased, but MBP was relatively spared. This might be due to the presence of large storage vesicles which interfere with protein transport of MAG, PLP and CNP, while MBP translation is at the site of insertion into the myelin. Bio-chemical and histologic analysis of white matter biopsies from 2 young girls with a progressive leuko-dystrophy due to unknown causes, revealed the presence of all the characteristic myelin proteins and lipids, but at significantly decreased amounts.